Clinical Features and Genetic Analysis of Autosomal Recessive Hypercholesterolemia

Abstract

Previously we have reported on siblings with severe hypercholesterolemia, xanthomas, and premature atherosclerosis without any impairment of low-density lipoprotein receptor in their fibroblasts as a first characterization of autosomal recessive hypercholesterolemia (ARH). Recently, mutations were identified for this disease in a gene encoding a putative adaptor protein. The purpose of this study was to examine the molecular pathogenesis of ARH in Japanese siblings. A novel insertion mutation was discovered in the ARH gene of the siblings. An insertion of an extra cytosine residue was identified in a locus comprising eight consecutive cytosines at positions 599 through 606 in exon 6, resulting in a sequence of nine cytosines and generating an early stop codon at 657-659. The mother was heterozygous for this mutation. Neither transcription product nor protein of ARH was detected in the fibroblasts of the homozygous patients. A single nucleotide polymorphism was discovered among the normal control subjects at position 604 (cytosine to thymine: ARH-604C to ARH-604T), which changes the proline residue at 202 to serine. Interestingly, ARH is caused by a mutation of cytosine to adenine at this same position. Both siblings exhibited fatty liver, which may also be related to this mutation.

Altered Metabolism of Low-Density Lipoprotein and Very-Low-Density Lipoprotein Remnant in Autosomal Recessive Hypercholesterolemia

“…19 An investigation, which extended back over 5 generations, failed to show any relationship between these 2 families, whose geographical origin were completely different. Using genetic analysis, we diagnosed 11 ARH heterozygous subjects and 6 normal subjects in the proband's family (Figure 2).…”

Guidelines for the Management of Familial Hypercholesterolemia

“…Homozygous ARH is also impossible to differentiate from homozygous FH based on clinical features of the patient. LDL receptor adapter protein 1 (LDLRAP1) is a gene causing ARH 61) , and heterozygous ARH is usually asymptomatic; therefore, the family history is important 62) . Sitosterolemia also causes xanthoma and…”

A Novel Thr56Met Mutation of the Autosomal Recessive Hypercholesterolemia Gene Associated with Hypercholesterolemia

“…All the reported mutations of ARH are predicted to introduce premature stop codons, either as a result of a point mutation or a frameshift. With these mutations, neither ARH mRNA nor ARH protein is detected, probably due to nonsense-mediated decay 7,12,14,16,25) . Thr56Met is a missense mutation, so it can be predicted that the production of normal levels of wildtype and mutant ARH protein would lead to competitive inhibition of binding to the LDLR.…”

“…In addition to binding with LDLR, ARH also binds to the 2-adaptin subunit of AP-2 and the terminal domain of clathrin via a specific sequence (LLDLE) in vitro, so it has been proposed that ARH may link LDLR to the endocytotic machinery 7,10) . Several researchers, including us, have identified various mutations of the ARH gene that cause autosomal recessive hypercholesterolemia 7,[11][12][13][14][15][16][17] , but it remains unknown whether this gene is relevant to common hypercholesterolemia. In the present study, we searched for single nucleotide polymorphisms (SNPs) of the ARH gene, including the 5'-flanking region, determined the haplotype structure for each polymorphism, and evaluated the association between ARH polymorphisms/haplotypes and hypercholesterolemia.…”